It is already known that the aqueous solubility of an active ingredient is a key parameter which governs its oral bioavailability. Lipophilic active ingredients and their pharmaceutically acceptable salts and derivatives are insoluble or practically insoluble in water and that results to low bioavailability of the active ingredient. Said lipophilic drugs have many disadvantages related to the fact that they are poorly absorbed from the gastrointestinal tract. Therefore, the improvement of the rate and extent of absorption of lipophilic drugs is highly desirable.
Moreover, drugs with low solubility in water (by which is meant having a solubility of less than 0.1 percent by weight in water at 20° C.) cause additional formulation problems due to their poor rate and extent of dissolution in aqueous media, including gastrointestinal fluids, which results in low absorption into systemic circulation after oral ingestion.
Various methods are already known to facilitate adequate absorption from the gastrointestinal tract and to increase the dissolution rate of oral dosage forms comprising a lipophilic active ingredient or salts and derivatives thereof. However, the prior art has encountered substantial difficulties in the production of the oral solid formulations of a desirable bioavailability.
In order to make a composition containing such a drug that will enable maximum absorption from the gastrointestinal tract, it is known to modify the crystalline structure of the active ingredient via micronization, spray drying or freeze drying or to modify the non-polarity of the active ingredient by alteration of the media in which the drug is dissolved.
However, the modification of the structure of the crystals can still not enable full dissolution and absorption of the active ingredient and unless said crystal modification is carefully controlled to be the same in every batch of the dosage form, release characteristics may vary from batch to batch.
Further, the modification of the media can be achieved by either adjusting the pH and/or the use of solubilizing agents, such as co-solvents, surfactants, complexing agents and oil/lipids.
However, the effect of such methods is not always satisfactory. For example, liquid lipid-based formulations need to be filled into soft gelatin capsules. This is not only an economical drawback but also raises capsule compatibility issues. Besides, some of the solubilizing agents are used in great quantities which might produce undesired side effects. Overall, these approaches are limited in the range and quantity of drugs which they can accommodate and also in their ability to promote the access of drug throughout the gastrointestinal wall.
Synthetic emulsions have also been used for oral administration of sparingly soluble drugs e.g. cyclosporine is formulated as a microemulsion. U.S. Pat. No. 5,447,961 discloses an oil-in-water type of emulsion containing milk for cosmetic purposes and U.S. Pat. No. 4,994,496 discloses the use of milk globules as carriers for drugs.
In addition, several documents denote the research on the solubility of lipophilic drugs in milk. The rate of dissolution of commercial formulations of lipophilic drugs in milk was found to be lower than the corresponding one in aqueous media. In another report, the rate of dissolution of lipophilic drugs used in a powder form was much higher in milk than in aqueous media. A series of in vitro and in vivo studies with reconstituted freeze-dried drug-milk formulations have demonstrated their superiority in regard to solubility and dissolution as well as the absorbability when compared to conventional capsule formulations of lipophilic drugs. Furthermore, it is known that food enhances the extent of absorption of lipophilic drugs.
Further, it is well known that a large number of drugs such as non-steroidal anti inflammatory drugs (NSAIDs) when taken orally in various dosage forms such as tablets, capsules, caplets, as well as chewable forms, create stomach irritation.
Although each of the above documents represents an attempt to overcome the problem of solubility of lipophilic drugs, there still exists a need for improving the bioavailability of a pharmaceutical composition containing a lipophilic active ingredient with milk as a solubilizing/dispersing agent.